The proposed research will address the hypothesis that: 1) the ability to resist circulatory shock during sepsis is correlated with the phagocytic activity of the reticulo-endothelial system (RES) and 2) the underlying basis for this relationship resides in the ability of the RES to control the extent and consequences of intravascular coagulation and microaggregate formation. Modulation of hemostasis and thrombosis is an important factor in maintaining vascular integrity and the hemostatic system is activated by sepsis. The phagocytic cells of the RES achieve such modulation by participation in the removal of activated coagulation factors, altered platelets, and fibrinogen derivatives from the circulation as well as participating in the fibrinolytic process. These functions have been correlated with the capacity of the RES to prevent vascular and tissue damage resulting from intravascular coagulation. These hypotheses will be studied by assessing the susceptibility toward circulatory shock in terms of deterioration of circulatory function and lethality when experimental sepsis is induced in rats whose RE function has been stimulated or depressed. Similar studies will be carried out during experimentally induced intravascular coagulation and platelet aggregation. Results will be interpreted in the context of the experimentally determined capacity of the RES to clear potentially embolizable thrombotic material and thus, limit the extent of peripheral circulatory embolization. The proposed research may provide both basic information relative to the mechanism by which a depressed RES predisposes to systemic deterioration during septic shock and may additionally provide support for the concept that management of RE function might be an important component of therapy for septic patients.